Fused bi- and tricyclic,di-,tridiaza-,and thiodiaza compounds

ABSTRACT

FUSED BI- AND TRICYCLIC, DI-, TRI- AND THIODIAZA COMPOUNDS, E.G. 2,3,3A, 10-TETRAHYDRO - 3 - PHENYLBENZOL(B) PYRROLO(2,3-E)(1,4)DIAZEPIN4(3H)-ONE PREPARED BY TREATING A CORRESPONDING SUBSTITUTED PYRIDINE OR PYRROLINE WITH A SUBSTITUTED ANILINE O-PHENYLENEDIAMINE, ETHYLENEDIAMINE OR DIAMINOPROPANE. THE COMPOUNDS ARE USEFUL AT TRANQUILIZERS AND HYPOTENSIVES.

United States Patent lice Patented Aug. 10, 1971 ABSTRACT OF THEDISCLOSURE Fused biand tricyclic, di-, triand thiodiaza compounds, e.g.2,3,3a,l-tetrahydro 3 phenylbenzo[b]pyrrolo[2,3-e] [1,4]diazepin-4(3H)-one prepared by treating a corresponding substitutedpyridine or pyrroline with a substituted aniline o phenylenediamine,ethylenediamine or diaminopropane. The compounds are useful attranquilizers and hypotensives.

This invention relates to substituted fused biand tricyclic, di-, triandthiodiaza compounds and to processes for their preparation.

The compounds of this invention may be represented by the followingstructural formula:

where X is S, or NH and m is 0 or 1;

R and R are independently, hydrogen, halo having an atomic weight offrom 19 to 36, 'trifluoromethyl, straight chain lower alkyl having 1 to3 carbon atoms, e.g. methyl, ethyl, or propyl, or straight chain loweralkoxy having 1 to 3 carbon atoms, e.g., methoxy, ethoxy, or propoxy;and

n is 1, 2 or 3;

provided that when one of R or R is trifluoromethyl, the other ishydrogen.

The compound of Formula I may also be represented by the followingstructural formulas:

H H R! N R1 N Tia-H R3 Rri[ W M D-n y\ \Q Ia Ib wherein R R R R X, m andn have the above stated significance.

The process for preparing the compounds of Formula Ia may be representedby the following reaction scheme A:

wherein R R R R X and n have the above stated significance and R islower alkyl having 1 to 3 carbon atoms, e.g., methyl, ethyl or propyl,isopropyl, with ethyl being preferred.

The compounds of Formula Ia are prepared by treating a compound ofFormula II with a compound of Formula III in an inert solvent such as alower alkanol having 1 to 3 carbon atoms, e.g., methanol, ethanol, orpropanol, an alkyl benzene, e.g., toluene, or Xylene, or mono ordichloro benzene and the like, in the presence of an inert gas e.g.nitrogen, helium or argon, at a temperature of from '60" C., to thereflux temperature of the solvent, preferably from about to C., forabout 2 to 96 hours, preferably 12 to 24 hours. Neither the solvents ortemperatures used are critical.

The process for preparing the compounds of Formula Ib may be representedby the following reaction scheme B:

where R R R m and n have the above stated significance.

The compounds of Formula Ib are prepared by treating a compound ofFormula II with a compound of Formula IV under the reaction conditionsand in the presence of the inert solvents described in scheme A.

The compounds of Formula Ib may be prepared in acid addition salt form,such as the hydrochloride, by conventional methods, such as suspendingthe compound in alcohol or water and treating with the appropriate acid.When it is desired to convert such salts to the corresponding freebases, conventional techniques may be utilized, e. g., dissolution ofthe salt in water and precipitation using a base such as sodiumhydroxide.

Standard techniques, e.g., crystallization, may be used to recovercompounds Ia and lb.

Certain of the compounds of Formulas II, III and IV are known and may beprepared by methods disclosed in the literature. Those compounds ofFormulas II, III and IV which have not been specifically disclosed maybe prepared by analogous methods from known materials.

It will be appreciated by those skilled in the art that when in (IH) Xis NH, and R and R are not equal, a mixture of compounds will result.The composition of the mixture will depend on the reaction conditions.

The compounds of Formula I, especially the compounds of Formulas Ia andlb wherein m is 0, are useful because they possess pharmacologicalactivity in animals. More particularly the compounds are useful astranquilizers as indicated by their ability to antagonize amphetamineinduced stimulation in mice, wherein the mice are each given 2.5milligrams per kilogram of body weight of amphetamine sulfate and 25milligrams to 200 milligrams per kilogram of active agent. The locomotoractivity of the mice is measured for an 80-minute period at -minuteintervals with an Actophotometer (manufactured by Woodard Res. Corp.,Herndon, Va.).

The compounds of Formula I, especially the compounds of Formulas Ia andlb where m is O, are also useful as hypotensives, as indicated by theiractivity in an anesthetized dog given 20 milligrams per kilogram IV ofactive agent and tested by blood pressure measurement using a mercurymanometer or transducer via a catheter inserted in the carotid orfemoral artery.

The compounds of Formula Ib may be administered in the form of theirnon-toxic pharmaceutically acceptable acid addition salts. Such saltspossess the same order of activity as the free base, are readilyprepared by reacting the base with an appropriate acid and accordinglyare included within the scope of the invention. Representative of suchsalts are the mineral acid salts, such as the hydrochloride,hydrobromide, sulfate, phosphate and the like and the organic acidsalts, such as the succinate, lbenzoate, acetate, p-toluenesulfonate,benzenesulfonate, maleate, malate, tartrate, methanesulfonate,cyclohexylsulfamate and the like.

The compounds (I) may be administered orally or parenterally and,depending upon the compound employed and the mode of administration, theexact dosage utilized may vary. In general, satisfactory results areobtained when these compounds are administered for the tranquilizer useat a daily dose of about 2 milligrams to about 100 milligrams perkilogram of animal body weight. This daily dosage is preferablyadministered in divided doses 2 to 4 times a day, or in sustainedrelease form. For most large mammals such as primates, the total dailydosage is from about 150 milligrams to about 1200 milligrams. Dosageforms suitable for internal use comprise from about 37.5 milligrams toabout 600 milligrams of the active compound in intimate admixture with asolid or liquid pharmaceutically acceptable carrier or diluent.

For the hypotensive use, satisfactory results-are obtained when thesecompounds are administered at a daily dose of about 3 milligrams toabout 150 milligrams per kilogram of animal body weight. This dailydosage is preferably administered in divided doses 2 to 4 times a day,or in sustained release form. For most large mammals such as primates,the total daily dosage is from about 200 milligrams to about 1600milligrams. Dose forms suitable for internal use comprise from about 50milligrams to about 800 milligrams of active compound in intimateadmixture with a solid or liquid pharmaceutically acceptable carrier ordiluent.

A representative formulation suitable for oral administration is atablet prepared by standard tabletting techniques which contains thefollowing:

Ingredients: Parts by weight 2,3,3a,1() tetrahydro 13phenylbenzo[b]pyrrolo [2,3-e] 1,4] diazepin-4( 3 -one Magnesium stearate0.5

This invention is illustrated but not limited by the following examples.

4 EXAMPLE 1 3 ,4,4a,l l-tetrahydro-2H-benzo[b] pyrido [2,3-e] [1,4]diazepin-S 6H -one OH n EXAMPLE 2 2,3 ,4,4a-tetrahydrobenzo [b] pyrido3,2-f] [1,4] thiaZepin-S 6H -one A mixture of 2.0 g. of1-ethoxy-2-ethoxycarbonyl-3,4, 5,6-tetrahydropyridine and 1.25 g. of2-aminothiophenol in 40 cc. of xylene Was refluxed under an atmosphereof nitrogen for 18 hours. Then the solvent was evaporated and the liquidsolidified. The product,2,3,4,4a-tetrahydrobenzo[b]pyrido[3,2-f][l,4]thiazepin 5 (6H) one, wasrecrystallized from methanol by addition of ether; M.P. 127 C.

EXAMPLE 3 2,3,321,l0-tetrahydro-3-phenylbenzo[b] pyrrolo[2,3-e][1,4]diazepin-4(3H)-one A mixture of 5.2. g. of2-ethoxy-3-ethoxycarbonyl-4- phenyl-2-pyrroline-1, 2.2 g. ofo-phenylenediamine in 50 cc. of absolute ethanol was refluxed under anatmosphere of nitrogen for 24 hours. The solvent was evaporated underreduced pressure. The product, 2,3,3a,l0-tetrahydro- 3phenylbenzo[b]pyrrolo[2,3-e][l,4]diazepin 4(3H)- one was recrystallizedfrom acetone by the addition of hexane, M.P. 22923l C.

EXAMPLE 4 13,3a-dihydro-3-phenyl-2H-benzo [b] pyrrolo[3,2-f] 1,4]thiazepin-4(5H) -one A mixture of 2-ethoxy--ethoxycarbonyl-4-phenyl-pyrroline (65 g.) was refluxed under anatmosphere of nitro gen for 18 hours with 28 g. of 2-aminothiophenol in250 cc. of absolute ethanol. When the solvent was cooled in an ice batha solid precipitated. Recrystallization from methanol yielded theproduct, 3,3a-dihydro-3-phenyl-2H- benzo[b]pyrrolo[3,2-f] [l,4]thiazepin4(5H) one; M.P. l53 C.

EXAMPLE 5 Using the conditions of Example 1, but in place ofo-phenylenediamine, starting with,

(a) 4-chloro-o-phenylenediamine,

(b) 4,5-dimethyl-o-phenylenediamine,

(c) 4,5-dimethoxy-o-phenylenediamine, (d)4-trifluoromethyl-o-phenylenediamine,

the following products are obtained:

(a) 8-chloro-3,4,4a,l l-tetrahydro-ZH-benzo [b] pyrido [2,3-e] [1,4]diazepin-S 6H -one,

(b) 3,4,4a,1 1-tetrahydro-8,9-dimethyl-2H-benzo [b] pyrido [2,3-e] [1,4]diazepin-S 6H)-one,

(c) 3,4,4a,1 1-tetrahydro-8,9-dimethoxy-2H-benzo [b] pyrido[2,3-e] [1,4]diazepin-S 6H)-one,

(d) 8-trifiuoromethyl- 1 ,3,4,4a,1 l-tetrahydro-ZH-benzo [b] pyrido[2,3-e] [1,4] diazepin-S 6H -one, respectively.

EXAMPLE 6 Using the conditions of Example 1, but in place of2-ethoxy-3-ethoxycarbonyl 3,4,5,6 tetrahydropyridine, starting with 2ethoxy 3 ethoxycarbonyl 4,5,6,7- tetrahydro 3H azepine, the product2,3,4,5,5a,11-hexa hydrobenzo[b]azepino[2,3-e] [1,4]diazepin 6(7H) oneis obtained.

EXAMPLE 7 1,2,3,4,5a,6,7,8-octahydropyrido [2,3-e] [1,4] diazepin-S (5H)-one A mixture of 4.0 g. of 2-ethoxy-3-ethoxycarbonyl-3,4,5,6-tetrahydropyridine and 1.3 g. of ethylenediamine was refluxedunder an atmosphere of nitrogen for 18 hours in 30 cc. of absoluteethanol. Upon evaporation of the solvent a white solid precipitated.Acetone 'was added and the solid was filtered off. The solid was heatedwith 25 cc. of hot acetone and filtered. The product, 1,2,3,4,5a, 6,7,8octahydropyrido[2,3-e][1,4-]diazepin-5(5H)-one, was recovered; M.P.174-l78 C.

EXAMPLE 8 1,2,3 ,4,6,7-hexahydro-6-phenylpyrrolo [2,3-e]

[1,4] diazepin-S SaJH -one i t N to A mixture of 15.6 g. of2-ethoxy-3-ethoxycarbonyl4 phenylpyrroline and 3.8 g. of ethylenediaminewas refluxed under an atmosphere of nitrogen in 100 cc. of absoluteethanol for 18 hours. Then the solvent was evaporated under reducedpressure and dissolved in acetone. From this solution the product,1,2,3,4,6,7-hexahydro- 6-phenylpyrrolo [2,3-e] [1,4] diazepin-S (Sal-I)one, precipitated; M.P. 175176 C.

EXAMPLE 9 1,2,3,4,6a,7,8,9-octahydropyrido [2,3-b][1,5]diazocin-6(5H)-one A mixture of 3.0 g. of2-ethoxy-3-ethoxycarbonyl-3,4, 5,6-tetrahydropyridine, 1.5 g. of 1,3diaminopropane was refluxed in 40 cc. of toluene under an atmosphere ofnitrogen for 20 hours. The solvent was evaporated under reduced pressureand the liquid solidified overnight. Recrystallization fromacetone/hexane (1:1) yielded the product,1,2,3,4,6a,7,8,9-octahydropyrido[2,3-'b] [1,5]-diazocin-6(5H)-one; M.P.161-164 C.

EXAMPLE 10 2,3 ,4, 5 ,7, 8-hexahydro-7-phenyllH-pyrrolo- [2,3-b] [1,5diazocin-6 6aH) -one What is claimed is: 1. A compound of the formulawherein R and R are independently hydrogen or phenyl;

R and R are independently, hydrogen, halo having an atomic weight offrom 19 to 36, trifiuoromethyl, straight chain lower alkyl having 1 to 3carbon atoms, or straight chain lower alkoxy having 1 to 3 carbon atoms,and

n is 1, 2, or 3 or a pharmaceutically acceptable acid addition saltthereof; provided that where one of R or R is trifluoromethyl,

the other is hydrogen.

2. The compound of claim 1 which is3,4,4a,11-tetrahydro-2H-benzo[b]pyrido[2,3-e] [1,4]diazepin 5 (6H,)-one.

3. The compound of claim 1 which is 2,3,3a,10-tetrahydro 3phenylbenzo[b]pyrrolo[2,3-e] [1,41diazepin-4- (3H)-one.

4. The compound of claim 1 which is 8-chloro-3,4,4a, ll-tetrahydro2H-benzo[b]pyrido[2, 3-e] [1,4]diazepin- 5(6H)-one.

5. The compound of claim 1 which is 3,4,4a,11-tetrahydro-8,9,dimethyl 2Hbenzo [b]pyrido[2,3-e] [1,4] diazepin-5 6H) -one.

6. The compound of claim 1 which is 3,4,4a,1l-tetrahydro-8,9-dimethoxy2H benzo[b]pyrido[2,3-e][1,4] diazepin-S 6H) -one.

7. The compound of claim 1 which is S-trifiuoromethyl-3,4,4a,l1-tetrahydro 2H benzo[b]pyrido[2,3-e][1,4] diazepin-S 6H) -one.

8. The compound of claim 1 which is 2,3,4,5,5a,l1-hexahydrobenzo[b]azepino[2,3-e] [1,4]diazepin 6(7H)- one.

7 9. The process for preparing a compound of claim 1 in free base formwhich comprises treating in an inert solvent and in the presence of aninert gas a compound of the formula R COORs with a compound of theformula t) Rs iii 10. A compound of the formula 0 in. E d --R;

l til wherein R and R are each, independently, hydrogen or phenyl;

R and R are each, independently, hydrogen, halo having an atomic weightof from 19 to 36, trifluoromethyl, straight chain lower alkyl having 1to 3 carbon atoms, or straight chain lower alkoxy having 1 to 3 carbonatoms, and

provided that when one of R or R is trifluoromethyl,

the other is hydrogen.

References Cited UNITED STATES PATENTS 3,316,251 4/1967 Schmidt 26O239.3

HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner US. Cl.X.R.

260239.3B, 239BE, 294.8B, 321R, 326.5SA, 326.5B, 1326.5R, 295.5R,326.12; 424-244, 267, 274, 275

